Navigating to the most promising directions amid complex fields of vaccine development: a chlamydial case study

ABSTRACT

Background: Vaccine-development research is proliferating making it difficult to determine the most promising vaccine candidates. Exemplary of this problem is vaccine development against Chlamydia, a pathogen of global public health and financial importance.

Methods: We systematically extracted data from studies that included chlamydial load or host immune parameter measurements, estimating 4,453 standardized effect sizes between control and chlamydial immunization experimental groups.

Results: Chlamydial immunization studies most often used (78%) laboratory mouse models. Depending on chlamydial species, single and multiple recombinant protein, viral and bacterial vectors, dendritic transfer, and dead whole pathogen were most effective at reducing chlamydial load. Immunization-driven decrease in chlamydial load was associated with increases in IFNg, IgA, IgG1, and IgG2a. Using data from individual studies, the magnitude of IgA and IgG2a increase was correlated with chlamydial load reduction. IFNg also showed this pattern for C. trachomatis, but not for C. muridarum. We also reveal the chlamydial vaccine development field to be highly bias toward studies showing these effects, limiting lessons learned from negative results.

Conclusions: Most murine immunizations against Chlamydia reduced chlamydial load and increased host immune parameters. These methods are novel for vaccine development and are critical in identifying trends where large quantities of literature exist.

KEYWORDS:

• Effect size
• immunization
• meta-analysis
• muridarum
• systematic search
• trachomatis

Article Highlights

• The number of vaccine development studies has increased in recent years resulting in large quantities of experimental results, making it difficult to identify the most efficacious vaccine candidates.

• We undertook a systematic review of vaccine candidates against Chlamydia, a field where a vaccine for humans does not yet exist.

• Our analysis shows the most effective vaccine candidates (immunizations) that reduce host chlamydial load are single and multiple recombinant proteins, viral and bacterial vectors, dendritic cell adoptive transfer, and dead whole pathogen immunizations.

• Additionally, most immunizations increased key anti-Chlamydia host immune parameters (IFNg, IgA, IgG1, or IgG2a).

• We found a correlation between the average IgA or IgG2a increase and average chlamydial load decrease after immunization against C. muridarum or C. trachomatis.

• Across all studies, we found a relationship between average chlamydial load decrease and average IFNg increase for immunizations against C. trachomatis, but not for immunizations against C. muridarum; likely complicated by the difficulty in measuring IFNg.

• The chlamydial vaccine development field is highly bias toward studies showing chlamydial load reductions and immune parameter increases, limiting lessons learned from unpublished studies and experiments where negative results were obtained.

• This study shows which vaccine candidates most effectively reduced chlamydial load, however, other factors such as disease prevention, delivery route, adjuvant usage, and protection against multiple chlamydial serovars should be considered in future studies.

• The methods used in this study can be applied to identify effective vaccine candidates against other pathogens where a vaccine does not currently exist (e.g. Neisseria gonorrhoeae and HIV).

Author contribution

All authors conceived the study design, D Lizárraga performed the systematic review and meta-analysis, and all authors contributed to interpreting the results and drafting of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary Material

The supplemental data for this article can be accessed here.

Additional information

Funding

This paper was funded by the Australian Research Council (to Peter Timms and Scott Carver) LP160100138.